Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardial injury

Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 10/2008; 118(10):3503-12. DOI: 10.1172/JCI35111
Source: PubMed

ABSTRACT Emerging metabolomic tools have created the opportunity to establish metabolic signatures of myocardial injury. We applied a mass spectrometry-based metabolite profiling platform to 36 patients undergoing alcohol septal ablation treatment for hypertrophic obstructive cardiomyopathy, a human model of planned myocardial infarction (PMI). Serial blood samples were obtained before and at various intervals after PMI, with patients undergoing elective diagnostic coronary angiography and patients with spontaneous myocardial infarction (SMI) serving as negative and positive controls, respectively. We identified changes in circulating levels of metabolites participating in pyrimidine metabolism, the tricarboxylic acid cycle and its upstream contributors, and the pentose phosphate pathway. Alterations in levels of multiple metabolites were detected as early as 10 minutes after PMI in an initial derivation group and were validated in a second, independent group of PMI patients. A PMI-derived metabolic signature consisting of aconitic acid, hypoxanthine, trimethylamine N-oxide, and threonine differentiated patients with SMI from those undergoing diagnostic coronary angiography with high accuracy, and coronary sinus sampling distinguished cardiac-derived from peripheral metabolic changes. Our results identify a role for metabolic profiling in the early detection of myocardial injury and suggest that similar approaches may be used for detection or prediction of other disease states.

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Available from: Gregory D Lewis, Sep 28, 2015
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    • "Lewis et al. [53] 2008 Case–control (36 patients undergoing alcohol septal ablation treatment compared to 16 elective diagnostic coronary angiography and 12 patients with MI) "
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    ABSTRACT: Insights from the “-omics” science have recently emphasized the need to implement an overall strategy in medical research. Here, the development of Systems Medicine has been indicated as a potential tool for clinical translation of basic research discoveries. Systems Medicine also gives the opportunity of improving different steps in medical practice, from diagnosis to healthcare management, including clinical research. The development of Systems Medicine is still hampered however by several challenges, the main one being the development of computational tools adequate to record, analyze and share a large amount of disparate data. In addition, available informatics tools appear not yet fully suitable for the challenge because they are not standardized, not universally available, or with ethical/legal concerns. Cardiovascular diseases (CVD) are a very promising area for translating Systems Medicine into clinical practice. By developing clinically applied technologies, the collection and analysis of data may improve CV risk stratification and prediction. Standardized models for data recording and analysis can also greatly broaden data exchange, thus promoting a uniform management of CVD patients also useful for clinical research. This advance however requires a great organizational effort by both physicians and health institutions, as well as the overcoming of ethical problems. This narrative review aims at providing an update on the state-of-art knowledge in the area of Systems Medicine as applied to CVD, focusing on current critical issues, providing a road map for its practical implementation.
    European Journal of Internal Medicine 10/2014; 25(9). DOI:10.1016/j.ejim.2014.09.015 · 2.89 Impact Factor
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    • "Metabolomics is a systems biology strategy for exploring the low molecular weight metabolites present in the metabolome of an organism [23]. It portrays a dynamic interaction of a phenotype with the environment, across genomic and post-transcriptional regulation [23] and has been applied to study cardiovascular diseases [24]–[29] including heart failure [30], myocardial ischemia [31], [32], myocardial infarction [33] and preeclampsia [34]. Its application in the investigation of glucose intolerance [35]–[38] has led to the identification of new metabolic biomarkers and has highlighted the influence of drugs on the metabolic profile of subjects diagnosed with glucoregulatory disorders [39], [40]. "
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    ABSTRACT: Background Blood-vessel dysfunction arises before overt hyperglycemia in type-2 diabetes (T2DM). We hypothesised that a metabolomic approach might identify metabolites/pathways perturbed in this pre-hyperglycemic phase. To test this hypothesis and for specific metabolite hypothesis generation, serum metabolic profiling was performed in young women at increased, intermediate and low risk of subsequent T2DM. Methods Participants were stratified by glucose tolerance during a previous index pregnancy into three risk-groups: overt gestational diabetes (GDM; n = 18); those with glucose values in the upper quartile but below GDM levels (UQ group; n = 45); and controls (n = 43, below the median glucose values). Follow-up serum samples were collected at a mean 22 months postnatally. Samples were analysed in a random order using Ultra Performance Liquid Chromatography coupled to an electrospray hybrid LTQ-Orbitrap mass spectrometer. Statistical analysis included principal component (PCA) and multivariate methods. Findings Significant between-group differences were observed at follow-up in waist circumference (86, 95%CI (79–91) vs 80 (76–84) cm for GDM vs controls, p<0.05), adiponectin (about 33% lower in GDM group, p = 0.004), fasting glucose, post-prandial glucose and HbA1c, but the latter 3 all remained within the ‘normal’ range. Substantial differences in metabolite profiles were apparent between the 2 ‘at-risk’ groups and controls, particularly in concentrations of phospholipids (4 metabolites with p≤0.01), acylcarnitines (3 with p≤0.02), short- and long-chain fatty acids (3 with p< = 0.03), and diglycerides (4 with p≤0.05). Interpretation Defects in adipocyte function from excess energy storage as relatively hypoxic visceral and hepatic fat, and impaired mitochondrial fatty acid oxidation may initiate the observed perturbations in lipid metabolism. Together with evidence from the failure of glucose-directed treatments to improve cardiovascular outcomes, these data and those of others indicate that a new, quite different definition of type-2 diabetes is required. This definition would incorporate disturbed lipid metabolism prior to hyperglycemia.
    PLoS ONE 09/2014; 9(9):e103217. DOI:10.1371/journal.pone.0103217 · 3.23 Impact Factor
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    • "In recent years, global metabolite profiling has been performed to gain insights into additional metabolic pathways active during periods of myocardial stress, e.g. ischemia [1]–[3], infarction [4], and exercise [5]. These studies have demonstrated that the circulating metabolites change in response to such perturbations. "
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    ABSTRACT: Objective: To determine whether increases in cardiac work lead to alterations in the plasma metabolome and whether such changes arise from the heart or peripheral organs. Background: There is growing evidence that the heart influences systemic metabolism through endocrine effects and affecting pathways involved in energy homeostasis. Methods: Nineteen patients referred for cardiac catheterization were enrolled. Peripheral and selective coronary sinus (CS) blood sampling was performed at serial timepoints following the initiation of pacing, and metabolite profiling was performed by liquid chromatography-mass spectrometry (LC-MS). Results: Pacing-stress resulted in a 225% increase in the median rate? pressure product from baseline. Increased myocardial work induced significant changes in the peripheral concentration of 43 of 125 metabolites assayed, including large changes in purine [ adenosine (+99%, p = 0.006), ADP (+42%, p = 0.01), AMP (+79%, p = 0.004), GDP (+69%, p = 0.003), GMP (+58%, p = 0.01), IMP (+50%, p = 0.03), xanthine (+61%, p = 0.0006)], and several bile acid metabolites. The CS changes in metabolites qualitatively mirrored those in the peripheral blood in both timing and magnitude, suggesting the heart was not the major source of the metabolite release. Conclusions: Isolated increases in myocardial work can induce changes in the plasma metabolome, but these changes do not appear to be directly cardiac in origin. A number of these dynamic metabolites have known signaling functions. Our study provides additional evidence to a growing body of literature on metabolic 'cross-talk' between the heart and other organs.
    PLoS ONE 06/2014; 9(6):e99058. DOI:10.1371/journal.pone.0099058 · 3.23 Impact Factor
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